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Modified dose intensive R- CODOX-M/IVAC for HIV-associated burkitt (BL) (AMC 048) shows efficacy and tolerability, and predictive potential of IRF4/MUM1 expression
Infectious Agents and Cancer volume 7, Article number: O14 (2012)
HIV associated BL remains of concern for toxicity of dose-intensive regimens used in HIV negative patients (pts). Less intensive regimens have a high relapse rate. We modified CODOX-M/IVAC hoping to preserve efficacy while improving tolerability, particularly treatment related mortality (TRM). Primary object: improving 1 year overall survival (OS) from the historical 65 to 85%.
Modifications of the US NCI regimen include rituximab (R), cyclophosphamide reduction [800 mg/m2 x 2 days], vincristine 2 mg cap, methotrexate (mtx) 3000 mg/m2, dual chemotherapy lumbar punctures and IVAC infusion (high risk pts). Antibiotic prophylaxis & growth factor support specified, 100% grade IV hematopoietic toxicities in the original regimen. HAART therapy at the discretion of the local MD. Pathology review included CD20, CD10, BCL2, BCL6, p53, Ki67, BLIMP1, IRF4/MUM1 and EBV EBER. (Table 1)
Accrual of 33 planned pts by April 2010. Baseline: Classical Burkitt, 97%; Low/High Risk, 9/91%; Median (range) Age 42 (19 – 55); CD4 count 195 (0 - 721), CD4 <100, 5 (27%); HIV viral load 1819 (Undetectable – 1,187,968). Median follow up (fu) is 9 mos for surviving pt. Number of pts with gr3/4 toxicity: any 20 (61%), 13 (39%) hematologic, 16 (48%) infection including 7 febrile neutropenia, 6 metabolic with 1 tumor lysis syndrome, 4 neurologic, 2 thrombotic and 1 each coagulation, GI or pain. Only 2 gr 1/2 stomatitis/mucositis; 0 had gr 3/4. Six deaths: encephalopathy with hepatic failure, hepatitis B and pneumonia (1), disease progression (3) including 1 in the CNS; fungal infection (1); HIV. Median 1 year OS (n=34) was 81.7% (61.0%, 92.1%) with a 35 mo median survival. OS by non-BL defining proteins: EBER +/- (8/16) and p53 +/- (10/10) were not predictive. IRF4/MUM1 +/- (8/15) highly predictive in overall pts, but not in the confirmed Burkitt +/- (6/14) with only 1 IRF4/MUM1 neg pt dying of BL.
AMC 048 with a median fu of 9 mos has a 1 yr OS of 82% in BL. Relapses after 1 year are rare. TRM was zero. R did not appear to increase toxicity. Only 5 pts withdrew due to AEs. Grade 3/4 toxicities were markedly reduced. Results compare favorably with 2 studies of HIV neg pts. Magrath (1995) reported 100% grade 4 hematologic and 20% grade 4 mucositis in 39 adults, 33 children (92% 2 yr EFS). MRC/NCRI LY10 trial (Mead 2008) reduced mtx (3gr/m2), but reported 9% TRM (64% 2 yr OS). IRF4/MUM1 deserves further study in BL.
This study is presented on behalf of the AIDS Malignancy Consortium.
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Noy, A., Kaplan, L., Lee, J. et al. Modified dose intensive R- CODOX-M/IVAC for HIV-associated burkitt (BL) (AMC 048) shows efficacy and tolerability, and predictive potential of IRF4/MUM1 expression. Infect Agents Cancer 7, O14 (2012). https://doi.org/10.1186/1750-9378-7-S1-O14
- Overall Survival
- Febrile Neutropenia
- Tumor Lysis Syndrome
- High Relapse Rate
- Treatment Related Mortality